Submissions for variant NM_000335.5(SCN5A):c.5848G>T (p.Val1950Leu)

dbSNP: rs41315493

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171770	SCV000055297	likely benign	Atrial fibrillation; Brugada syndrome	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041632	SCV000065328	benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	p.Val1951Leu in Exon 28 of SCN5A: This variant is not expected to have clinical significance because it has been identified in 6.5% (6/92) of chromosomes from a population in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP; rs4 1315493).
Eurofins Ntd Llc (ga)	RCV000041632	SCV000114839	benign	not specified	2013-07-05	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000041632	SCV000257779	benign	not specified	2015-07-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000058811	SCV000260075	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000041632	SCV000306552	likely benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000245882	SCV000318649	benign	Cardiovascular phenotype	2015-08-05	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Athena Diagnostics	RCV000058811	SCV000843725	benign	not provided	2017-10-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001841551	SCV000910998	benign	Cardiac arrhythmia	2018-03-19	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000058811	SCV000987699	likely benign	not provided		criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852961	SCV000995710	benign	Cardiomyopathy; Long QT syndrome	2019-06-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000058811	SCV001157223	benign	not provided	2023-08-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001145802	SCV001306498	likely benign	Dilated cardiomyopathy 1E	2018-02-05	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001148560	SCV001309465	likely benign	Progressive familial heart block, type 1A	2018-02-05	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001148561	SCV001309466	likely benign	Long QT syndrome 3	2018-02-05	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001148562	SCV001309467	likely benign	Ventricular fibrillation, paroxysmal familial, type 1	2018-02-05	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001148563	SCV001309468	benign	Sick sinus syndrome 1	2018-02-05	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001148564	SCV001309469	likely benign	Brugada syndrome 1	2018-02-05	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149588	SCV003838216	benign	Cardiomyopathy	2021-12-13	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000058811	SCV005258469	likely benign	not provided		criteria provided, single submitter	not provided
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030444	SCV000053113	benign	Long QT syndrome	2015-01-08	no assertion criteria provided	clinical testing	Variant Summary: c.5848G>T is a missense variant that occurrs at a non-conserved position, and 5/5 in silico tools predict benign outcome of this variant. The observed allele frequency in an ethnically diverse set of control chromosomes is 102/24,730 (1/242; 0.41%; 2 homozgotes reported); this frequency is significantly higher than the maximal expected allele frequency of 1/48,000 for a pathogenic SCN5A variant for LQTS/SCD or 1/6,000 for BrS. The ExAC population reports the variant in 477/11,174 (1/23; 4.27%) Latino chromosomes, with 6 homozygotes. These allele frequencies strongly suggest that the variant is benign. Further support of a benign outcome is a reported Korean family (Shin et al, 2003) where this variant did not cosegregate with disease, and a sudden cardiac death patient whom also carried another potentially pathogenic variant in the KCNE1 gene (Tester et al 2012). Functional studies results are in conflict, but suggest that the variant may have a modifying effect dependent upon the presence of other SCN5A variants. Most in vitro studies have shown that the variant has no significant effect on in vitro function when in isolation. V1951L did not exhibit an overt LQT3-like phenotype or an overt loss of function phenotype, therefore its involvement in the settings of either LQT3 or Brugada syndrome is not substantiated. Furthermore, although the authors reported other "significant functional disturbances" , the results and conclusions of these findings are not applicable to the mechanism of action, and physiologic consequences or presentation of disease (i.e., LQT3 or Brugada). Collectively, although this variant may play a role in the context of complex or oligogenic alleles, in isolation there is no evidence to suggest that it significantly impairs SCN5A function, several reputable sources classify the variant as benign, and the significantly higher oberseved allele frequency compared to the maximimal expected allele frequency of a pathogenic SCN5A variant indicate that the in vivo consequence of this variant is, indeed, benign.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058811	SCV000090331	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:10807545;PMID:11901046;PMID:15851227;PMID:16379539;PMID:17210839;PMID:18426444;PMID:19841300;PMID:21109022;PMID:20129283;PMID:15992732;PMID:17210841;PMID:22378279).
CSER _CC_NCGL, University of Washington	RCV000148837	SCV000190578	likely benign	Brugada syndrome	2014-06-01	no assertion criteria provided	research
Blueprint Genetics	RCV000157493	SCV000207238	likely benign	Pulmonary valve stenosis (rare); Ventricular tachycardia	2014-08-15	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000041632	SCV000280480	uncertain significance	not specified	2015-03-26	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Val1951Leu (c.5851G>T) in the SCN5A gene. This variant has been reported in published literature. Priori et al (2004) reported the presence of the variant in one Caucasian individual who had a Brugada syndrome diagnosis. It was also reported in a case of SIDS (Arnestad et al 2007). In vitro studies have been conflicting, with some reporting an abnormal biophysical phenotype (Wang er al 2008) and others reporting normal function (Tan et al 2005). Arnestad et al commented that this variant could exhibit ethnic-dependent phenotype expression (2007). A nonpolar, neutral Valine is replaced with a nonpolar, neutral Leucine at position 1951 in the SCN5A gene. The change does not affect the net charge of the polypeptide. This codon is not well conserved across species. In 2004, Darbar et al sequenced the SCN5A coding region of 378 individuals with Atrial fibrillation (alone or in association with another cardiac condition), they identified one Caucasian individual with atrial fibrillation and HCM who harbored a variant in the same codon (p.Val1951Met). In this patient’s family the variant did co segregate with phenotype in the patient’s father, paternal grandmother and 2 siblings. Priori et al (2004) report this variant was not found in 400 Caucasian presumably healthy controls. Genedx did not find the variant in 200 Caucasian and African American controls. However, the p.Val1951Leu variant has been reported in 6.7% of normal Hispanics (Ackerman et al 2005). Darbar et al (2008) reported that the p.Val1951Leu variant was observed in 7 out of 720 presumably healthy controls of both Caucasian and African American descent. In addition, Kapplinger et al (2010) reported that the p.Val1951Leu variant is found in highest percentage in Hispanic controls, then Asian, African America and “other” presumably healthy controls. They classified this variant as a polymorphism. Given these data, the impact of this variant on arrhythmic risk is unclear. It is possible that it is a common variant (i.e. >5%) in several ancestral groups and that it was identified in the published cases of SIDS and Brugada because of its prevalence, not because of its pathogenicity.
Clinical Genetics, Academic Medical Center	RCV000041632	SCV001923433	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000041632	SCV001931515	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000041632	SCV001956429	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000041632	SCV001974460	benign	not specified		no assertion criteria provided	clinical testing